Thursday, 29 January 2015

IS timing of Optic Neuritis eye damage and slow treatment why drugs are showing no effect

Gabilondo I, Martínez-Lapiscina EH, Fraga-Pumar E, Ortiz-Perez S, Torres-Torres R, Andorra M, Llufriu S, Zubuizarreta I, Saiz A, Sanchez-Dalmau B, Villoslada P.Dynamics of retinal injury after acute optic neuritis. Ann Neurol. 2015 Jan. doi: 10.1002/ana.24351. [Epub ahead of print]

Background: We set out to assess the dynamics of retinal injury after acute optic neuritis (ON), and their association with clinical visual outcomes. 
Methods: 31 consecutive patients with acute ON were prospectively analyzed over a 6 month follow-up period. Each month, we used Optical Coherence Tomography (OCT) to assess the thickness of peripapillary retinal nerve fiber layer (pRNFL) and segmented macular layers, as well as high contrast, low contrast (LCVA) and colour visual acuity (CVA), and visual fields (VF). Results: In this prospective study, we found that 6 months after clinical onset, ON-eyes suffered a reduction in pRNFL (-45.3 µm) and macular thickness (-17.3 µm). Macular atrophy was due to the decrease of macular RNFL thickness (-7.8 µm) and that of the ganglion cell layer and inner plexiform layer (GCIP, -11.3 µm), while the thickness of the outer retinal layers increased slightly. The macular RNFL and GCIP thickness decreased in parallel, yet it always occurred more rapidly and more severely for the GCIP. The change in the GCIP thickness in the first month predicted the visual impairment by month 6: a decrease ≥ 4.5 μm predicted poor LCVA (sensitivity of 93 % and specificity of 88%); and ≥ 7 μm predicted poor VF and CVA (sensitivity of 78% and 100% and specificity of 63% and 66%, respectively). 
Interpretation: Retinal axonal and neuronal damage develops quickly after ON onset. Assessment of ganglion cell layer thickness by OCT after ON onset can be used as an imaging marker of persistent visual disability. 
After optic neuritis which is an immune attack on the optic nerve and this is associated with retinal cell loss. There is thinning of the retinal ganglion cell layer and the inner nuclear Layer. This study shows that most of the damage is done within two months in fact in severe optic neuritis within one month.

Is this the reason why we have seen some recent failures in trials with riluzole, anti-LINGO-1 and Erythropoetin. Erythropoetin has been shown to work in optic neuritis but the recent trial failed
Waubant E, Maghzi AH, Revirajan N, Spain R, Julian L, Mowry EM, Marcus J, Liu S, Jin C, Green A, McCulloch CE, Pelletier D. A randomized controlled phase II trial of riluzole in early multiple sclerosis. Ann Clin Transl Neurol. 2014;1(5):340-7

Shayegannejad V, Shahzamani S, Dehghani A, Dast Borhan Z, Rahimi M, Mirmohammadsadeghi A.Graefes A double-blind, placebo-controlled trial of adding erythropoietin to intravenous methylprednisolone for the treatment of unilateral acute optic neuritis of unknown or demyelinative origin.Arch Clin Exp Ophthalmol. 2015 Jan. [Epub ahead of print]

There media hints that there was a hint that anti-LINGO-1 given up to one month after the attack promoted remyelination when this was asses
sed by electrical conduction from the eye to the brain. But nerves were not saved in the eye. 

Was this a failure?...yes in the eyes of people saying that remyelination should save nerves, but lack of protect of the nerve cells is surely what should have been expected. 

I think there is no real logic why anti-LINGO should block the inflammatory response from developing and no reason why the nerves should have been saved because anti-LINGO-1 has no logical proven neuroprotective effect. So is it going to stop nerve loss....probably not. It needs anti-inlammatories/neuroprotectors

In mice we and others have shown that nerve loss in the eyes starts within a few days of the onset of the inflammatory attack of the nerves and is complete within a week or so. So this current study shows that by the time treatment with anti-LINGO-1 was started a significant proportion of nerves would already be dead and so the drug would stand little to no chance of saving the nerve loss. 

So anti-LINGO-1 would have trouble remyelinating nerves that weren't there.

Lets avoid MS Drug Made by Science....Killed in the clinic.

6 comments:

  1. So will the Phenotoin trial also fail? To stop nerve loss we need to treat for the immune attack (?virus) and also stop the immune attack. Trying to protect nerves or remyelinate nerves after an attack is too late.

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  2. Maybe....as the study has ended it will have worked, not worked with or without a trend. We will have to wait until we have the results, the data I understand is being analysed and will be presented in 2015.

    Because of the animal data that we generated this indicated that treatment had to start as soon as possible, People in the study were seen, I think had an MRI and consented and randomised and on drug within 2 weeks of presenting their first symptom, which I think is pretty quick, if you think of your first symptom how long did it take to see a neurologist and be actively treated

    I think we have to give credit to Dr Kapoor and the team for getting the trial done so swiftly. We have to wait to see what this trial will show and how this will compare to the Amiloride study ongoing in Oxford, which started around the same time but I think is on-going but recruitment is much slower. In the anti Lingo study there were a huge number of sites compared to the phenytonin study which was done in London.

    This is key to the potential of doing these studies. We have a large academic (Moorfields) eye hospital...which has an A&E (ER) department for all things eye and MS neurologists (from Queen square) embedded within the eye hospital so there is an infrastructure to recruit and see a specialist quickly. Next London has a lot of people.

    People in the trial were all given steroids which are immunosuppressve and we have to remember that there is an anti-inflammatory effect by blocking microglia action which is part of the presumed mechanism of neuroprotection of the sodium channel blocker. However you are correct it still took up to two weeks. Our aim was to deliver drugs to the lesion (inflammatory penumbra) was actively developing. In mice this is about 5 days and based on MRI of MS lesions should be about 2-4 weeks in humans. The best effect would to have had a immunosuppresive DMT in the mix too and ideally a better sodium channel blocker, which is my worry.

    Phenytonin in our hands was one of the weaker neuroprotectors of the class, but it is a drug that can be given quickly. Some of the others would have to loaded slowly and thus take time. PROXIMUS, which is recruiting now, has an immunosuppressive (current treatment) and neuroprotecting sodium channel blocker on top, so if you are eligible please consider volunteering.

    However, what this current study suggests that much of the damage accumulates quickly and although the phenytonin trial was 6 months the data in this paper suggests that such trials do not have to be as long as most of the damage accumulates within 2 months so a trial could be shorter. So you could know if you have neuroprotective drugs within a few months rather than 2-5 years in a conventional trial in RRMS or progressive MS. Also maybe you don't need to treat for long.

    I hope the phenytonin trial works and then some of the trolls that frequent these webpages will need to eat them/it, rather than write them/it.....it's "words" isn't it:-).

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    Replies
    1. MD 2,

      Many thanks for your detailed response. My position is different as I received Alemtuzumab some eight years ago (first infusion). No relapses, MRI shows no inflammation / activity, EDSS stable. I have some deficits from the earlier relapse pre-Alemtuzumab. I still live with the fear of progressive disease plus would like to think that one day some of the deficits could be reversed (to some extent). Is neuro-protection still relevant for me if it became available? It looks a if the neuro-protection trials are being tested in RRMS e.g. with ON. I thought neuro-protection was for progressive patients i.e. to slow down or stop the slow death of nerves etc. If an sodium channel blocker was seen to have benefit, would this have to be taken for life or just after a relapse?

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    2. The idea is for progressive patients, but we have been asking how do we show the agents are neuroprotective quickly. We need to do progressive EAE study and we could try it in our model. The question I am putting to the neuros is what next? if it works.

      I wonder if Biogen got some new ones in their buy-out of the Company with the Nav 1.7 (Sodium channel 7) anti-pain drug. Maybe they have drugs that target Nav 1.6 (Sodium channel 6). I'ld like to test them please contact us.


      Anyway to address your comment the rapidly translatable effect would be to add-on to treatment during a relapse to stop damage and this could be transient treatment, but for progression we would need to think of long term treatment if we do not get effective repair.

      The problem with the sodium channel blockers are their side effects, but if we can show benefit with a sodium channel blocker I bet we can do it again with other things that are better tolerated.

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    3. Having seen the data presented in the paper here which looks at monthly scans, if only we got weekly scans early this could really tell us what the window of opportunity is. Maybe it is less than 2 weeks and that could be what the trial shows. But this information will really help on how to use the visual pathway to study remyelination. Maybe we need combinations, stop the nerve loss and then remyelinate..simples.

      Macular changes accumulate slow than RNFL changes is this a better outcome

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  3. This is off-topic but somewhat related - does anyone know why anterior iritis is more common in people with MS?
    I had 6 attackts of acute anterior iritis that went away with steroid eyedrops and was diagnosed with MS 6 months later after some tingling that started in the feet and spread to other limbs.

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